The use of murine monoclonal antibodies in medicine has significant potential especially in the diagnosis and treatment of various diseases, including cancer. The advantage of using monoclonal antibodies resides is their specificity for a single antigen. A monoclonal antibody raised against a specific tumor cell surface antigen can be coupled to therapeutic agents, such as radioisotopes and chemotherapeutic drugs, and these immunoconjugates can be used clinically to specifically target, for example, a tumor cell of interest.
A major limitation in the clinical use of monoclonal antibodies is the development of a human anti-murine antibody (HAMA) response in the patients receiving the treatments. The HAMA response can involve allergic reactions and an increased rate of clearance of the administered antibody from the serum. Various types of modified monoclonal antibodies have been developed to minimize the HAMA response while trying to maintain the antigen binding affinity of the parent monoclonal antibody. One type of modified monoclonal antibody is a human-mouse chimera in which a murine antigen-binding variable region is coupled to a human constant domain (Morrison and Schlom, Important Advances in Oncology, Rosenberg, S. A. (Ed.), 1989). A second type of modified monoclonal antibody is the complementarity determining region (CDR)-grafted, or humanized, monoclonal antibody (Winter and Harris, Immunol. Today 14:243-246, 1993). A more recent method in the humanization procedure is based on grafting, onto the variable (VL) and variable heavy (VH) frameworks of human monoclonal antibodies (mAb), of the specificity determining residues (SDRs), the CDR residues that are crucial for the complementarity of the antigen (Ag):Ab surfaces (Kashmiri et al., Crit. Rev. Oncol. Hematol. 38: 3-16, 2001). In generating humanized Abs, whether by grafting CDRs or SDRs, a few murine framework residues considered crucial for the maintenance of the Ab combining sites are also transplanted onto the human frameworks (for example, see Abola et al., Methods Enzymol 277, 556-71, 1997).
Murine CC49 (mCC49) is an antibody that specifically recognizes a tumor-associated glycoprotein (TAG)-72 expressed on a majority of human carcinomas (Muraro et al., Cancer Res. 48:4588-4596, 1988). These antibodies have been shown to efficiently target colorectal (Divgi et al., J Nucl Med 36:586-592, 1995; Divgi et al., Clin Cancer Res 1:1503-1510, 1995; Liu et al., Cancer Biother Radiopharm 12:79-87, 1997; Meredith et al., Clin Cancer Res 2:1811-1818, 1996; Rucker et al., J Immunother 22:80-84, 1999; Tempero et al., J Clin Oncol 15:1518-1528, 1997), breast (Macey et al., Clin Cancer Res 3:1547-1555, 1997; Murray et al., Cancer Res 55:5925s-5928s, 1995), ovarian (Alvarez et al., Gynecol Oncol 65:94-101, 1997; Meredith et al., Cancer Biother Radiopharm 16:305-315, 2001; Meredith et al., J Nucl Med 37:1491-1496, 1996), and prostate (Liu et al., Cancer Biother Radiopharm 12-7987, 1997; Meredith et al., Clin Cancer Res 5:3254s-3258s, 1999; Slovin et al., Clin Cancer Res 4:643-651, 1998) carcinomas in several phase I/II clinical trials. As a therapeutic reagent, humanized CC49 (177Lu-mCC49) has been found to evoke objective responses in ovarian cancer patients (Alvarez et aL, Gynecol Oncol 65:94-101, 1997; Meredith et al., Cancer Biother Radiopharm 16:305-315, 2001; Meredith et al., J Nucl Med 37:1491-1496, 1996), while objective responses have also been reported in metastatic breast and prostate cancer patients administered with one or two doses of 131I-mCC49 (Macey et al., Clin Cancer Res 30 3:1547-1555, 1997; Meredith et al., Clin Cancer Res 5:3254s-3258s, 1999). mCC49 has also been used in radioimmunoguided surgery, which is more sensitive in detecting metastases than the traditional clinical and histological examinations (Cote et al., Cancer 77:613-620, 1996; LaValle et al., Surgery 122:867-871, 1997; McIntosh et al., Cancer Biother Radiopharm 12:287-294, 1997), thus resulting in better disease staging (Haddad et al., Eur J Surg Oncol 27:298-301, 2001; Schneebaum et al., Recent Results Cancer Res 157:281-292, 2000).
Unfortunately, the clinical utility of the mCC49 monoclonal antibody has been limited because of its murine origin. Thus, there clearly exists a need to develop a humanized CC49 antibody with both high antigen binding affinity and low immunogenicity for use in human subjects.